#4113 Background: Estrogen modulates angiogenesis through effects on endothelial cells and by induction of vascular endothelial growth factor (VEGF) expression. Increased VEGF promotes tumor growth and is associated with a poor response to anti-estrogen therapy. This trial evaluates the impact of bevacizumab (B) combined with anastrozole (A) or fulvestrant (F) on progression free survival (PFS) as first line endocrine therapy in metastatic breast cancer (MBC).
 Methods: Study design: Two arm nonrandomized, noncomparative trial of A or F in combination with B. Eligibility: 0 prior hormonal or chemotherapy for MBC, measureable or evaluable disease, normal LVEF, postmenopausal, normal organ function. Treatment: Arm 1: Patients (pts) who either were endocrine therapy naïve, ≥ 12 months from adjuvant endocrine therapy, or who had intolerance to or progression on tamoxifen were treated with anastrozole 1 mg po daily. Arm 2: Patients who were ≤ 12 months from adjuvant aromatase inhibitors (AIs), intolerant of or progressed on adjuvant AIs, or at physician's discretion were treated with fulvestrant 500 mg IM loading dose, 250 mg D15 and every q28 days thereafter. B 10 mg/kg q2wks beginning day 1 was administered in both arms. Concurrent trastuzumab (T) was administered in HER2+ patients. Response assessments were performed q8 wks. Pts were treated until disease progression or toxicity.
 Results: 44 pts have been enrolled with data available for 29 pts. 18 pts (62%) were treated with anastrozole and 11 pts (38%) with fulvestrant. Median age: 64 yrs (range 44-88), ECOG PS 0-17 pts (59%) and PS 1 -12 pts (41%). 7 pts (24%) presented with de novo stage IV disease. 52% had 2 or more metastatic disease sites with bone metastases predominating 16 pts (55%), 7 pts (24%) with bone only disease. There were no G3/4 heme toxicities. G3/4 non-hematologic events consisted of G3 hypertension in 3 pts (10%), arthralgias 1 pt (3%), and CHF 1 pt (3%). This symptomatic LVEF of 40% occurred in arm 1 during cycle 3 and was noted to recover to 50-55% within 1 wk. This pt did not receive T. A median of 4.5 cycles have been administered. PRs were noted in 7 pts (24%) and 14 pts (48%) demonstrated SD. PD was noted in 3 pts and 5 pts were not yet evaluable. 73% of pts are progression free at 12 months. At a median follow up of 7.5 months, median PFS and overall survival has not been reached.
 Conclusions: The combination of bevacizumab with anastrozole or fulvestrant is feasible and well tolerated with adverse events as expected, reflecting standard bevacizumab related toxicities. Bevacizumab in combination with endocrine therapy is promising with early evidence of a high rate of clinical benefit at 72%. Further follow up is warranted. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4113.

Background: The frequency of AR expression varies in the different breast cancer subtypes with 88%, 59%, and 32% expression reported in ER+, HER2+, and triple negative tumors, respectively. AR expression is associated with resistance to endocrine therapy in ER+ breast cancer. Androgen levels frequently increase following treatment with aromatase inhibitors suggesting a role for androgen synthesis inhibitors in ER+ breast cancer. AR signaling and expression are seen in triple negative breast cancer (TNBC), and a distinct AR TNBC subtype can be identified by gene expression profiling. AR expression in TNBC offers a potential therapeutic target. Preclinical and clinical studies demonstrated anti-androgen agent activity in breast cancer cell lines; preliminary clinical data suggests activity in TNBC. Orteronel is a novel, oral, selective, nonsteroidal inhibitor of 17, 20-lyase, a key enzyme in androgen biosynthesis that is being evaluated as endocrine therapy in various hormone-sensitive cancers. In this phase 2 study we are evaluating single agent orteronel in AR+ MBC. Methods: Pts with AR expressing MBC (≥10% staining by central immunohistochemistry) were eligible. Pts were grouped into 2 cohorts for analysis: Cohort 1-TNBC and Cohort 2-ER+ (HER2 could be +/- in this cohort). Pts must have been previously treated with standard therapy for MBC (1-3 chemotherapy regimens for TNBC, 1-3 hormonal therapies + 1 chemotherapy for ER+ patients, ≥2 HER2-targeted regimens for HER2+ patients). A 6 pt lead-in for safety and tolerability of orteronel in AR+ female MBC pts was followed by open enrollment to either cohort. All pts received 300 mg orteronel PO BID over a 4 week cycle and underwent response assessment every 2 cycles. Treatment was continued until disease progression or unacceptable toxicity. The hypothesized response rate for Cohort 1 was 10% and 13% for Cohort 2. We present the results of a protocol-specified interim analysis of the ER+ MBC pts (Cohort 2). Results: From 3/2014 to 4/2015, a total of 29 pts were enrolled on cohort 2. Median age was 65 years (range, 39-79); 90% ECOG ≤1; 90% HER2-/10% HER2+; median of 7 prior therapies (range 3-11). 93% had prior chemotherapy. Pts received a median of 2 cycles of orteronel treatment (range 1-4) and 3 pts (10%) are still on treatment. Of the 26 pts (90%) pts that have discontinued, 19 (66%) discontinued due to disease progression, 4 (14%) due to pt decision, 2 (7%) due to adverse event (AE), and 1 (3%) due to non-compliance. The most common treatment-related G 3/4 AEs were increased lipase [3 pts (10%)] and hypertension [2 pts (7%)]. There were no treatment-related SAEs or deaths on study. Three pts (10%) had stable disease as their best response. Further response evaluation is underway. Conclusions: Orteronel monotherapy was well tolerated but appears to have limited single-agent activity in this heavily pre-treated ER+ MBC pt population. The full results from this interim analysis will be presented. Citation Format: Yardley DA, Peacock N, Young RR, Silber A, Chung G, Webb CD, Jones SF, Shastry M, Midha R, DeBusk LM, Hainsworth JD, Burris HA. A phase 2 study evaluating orteronel, an inhibitor of androgen biosynthesis, in patients with androgen receptor (AR)-expressing metastatic breast cancer: Interim analysis. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-14-04.

Background: Ixabepilone (Ixa) is active in anthracycline and taxane-refractory metastatic breast cancer as well as in the neoadjuvant setting where Ixa yielded a pathologic complete response (pCR) rate of 11%. In this study, we evaluated Ixa in combination with cyclophosphamide (C) as neoadjuvant treatment for ER+/ER- HER2−negative breast cancer. The primary endpoint was pathologic complete response (pCR) rate, defined as no residual invasive cancer in breast or lymph nodes. The Oncotype DX Breast Cancer Assay, that uses reverse transcriptase-polymerase chain reaction (RT-PCR) to assess a panel of 21 tumor genes to calculate a score predictive of the likelihood of the magnitude of adjuvant chemotherapy benefit, was applied to pretreatment and residual disease tumor samples obtained at the time of definitive surgery. The likelihood of whether neoadjuvant clinical or pathological responses may be predicted by Oncotype DX recurrence scores (RS®) was assessed. An interim analysis of the first 81 patients (pts) was reported at ASCO 2011. The final analysis will be presented on all 168 pts. Methods: Eligible women had locally advanced breast cancer that was HER2−negative (IHC 0–1+ or FISH negative), T >2 cm or lymph node positive. Pts with inflammatory breast cancer or T1N0 tumors were excluded. Pts received Ixa 40mg/m2 with C 600mg/m2 day 1 q21 days x6 cycles. Following 6 cycles, had definitive surgery. Postoperative locoregional radiation therapy and/or hormonal treatments were at discretion of the treating MD per institutional guidelines. Breast core biopsy tumor samples were obtained pretreatment and at the time of surgery in those pts demonstrating residual disease at surgery. Tumor specimens were analyzed using the Oncotype DX RT-PCR assay. An interim pretreatment RS assessment in the first 38 pts and paired samples in 21 pts was conducted and correlated with clinical and pathologic responses. Results: 168 women enrolled. Baseline characteristics and toxicity for the first 118 pts are reported (median age 52 years; 90% invasive ductal carcinoma; T2/T3 52%/31%; 42% triple negative). 81 pts have undergone surgery. 25 pts discontinued treatment early (toxicity — 12; disease progression — 8; pt/MD request — 3; pt non-compliance — 2).Grade 3/4 toxicity included: neutropenia (65%), leukopenia (47%), neuropathy (10%), and febrile neutropenia (7%). Preliminary toxicity results with this neoadjuvant treatment have been previously reported (Peacock et al, ASCO 2011 Abstract #1066). Oncotype DX pretreatment evaluations for the initial 38 pts demonstrated a significant logistic regression of pretreatment recurrence score with pCR (p = 0.025). Conclusions: Neoadjuvant therapy with Ixa and cyclophosphamide yielded a preliminary pCR rate of 19% (in 81 pts), similar to results with other 2-drug combination chemotherapy regimens. Preliminary Oncotype DX assessments at baseline indicated that baseline recurrence scores may predict pCR rates. These exploratory Oncotype DX recurrence scores at baseline and paired with scores obtained at the surgery and correlations with pCR will be presented for the entire cohort. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-13-09.

Background: Residual breast cancer after NAC is associated with a high risk of recurrence. Little evidence supports the use of further chemotherapy in this setting. Eribulin, an inhibitor of microtubule dynamics, demonstrated a survival advantage in patients with metastatic breast cancer who had progressed after previous anthracycline and taxane therapy. This phase 2 trial assessed the efficacy of eribulin (2-yr disease-free survival) administered postoperatively to breast cancer pts not achieving a pCR following standard NAC. Methods: Women with invasive breast cancer (stage T1-4b, N0-2, M0 at diagnosis) and evidence of residual cancer (>5 mm) in the breast or axillary lymph nodes (LN) following ≥4 cycles of standard anthracycline and/or taxane-containing NAC were eligible. Additional eligibility criteria: age ≥18 yrs, peripheral neuropathy < 1, adequate hematologic, hepatic, and renal function. 3 groups were studied: Cohort A-triple negative (TN), Cohort B-HR+/HER2-, Cohort C-HER2+. After recovery from definitive surgery, all pts received eribulin mesylate 1.4mg/m2 IV on days 1 and 8 every 21 days for 6 cycles. Cohort C pts also received trastuzumab 6mg/kg IV day 1 every 21 days for a total of 1 yr from start of NAC. Adjuvant hormonal therapy and loco-regional radiotherapy were administered per institutional guidelines. We hypothesized post-operative eribulin would result in a 40% increase over the reported 40% 2 yr DFS for TN, and a 15% increase over the reported 80% 2 yr DFS for HR+/HER2- pts who did not achieve pCR following standard NAC. Results: 127 pts were enrolled (54, Cohort A; 42, Cohort B; 31, Cohort C). Pts on Cohort C continue with study treatment. Here, we present the results of 95 pts treated on Cohorts A and B. Median age-52 yrs (range, 27-74). 87 pts (92%) had invasive ductal adenocarcinoma, 6 (6%) invasive lobular, 1 (1%) mucinous, and 1 (1 %) unknown; 34 pts (36%) had T3 or T4 tumors and 65 (68%) had N1-2 disease at diagnosis. NAC with anthracyclines was administered to 74 pts (78%), taxanes to 88 (93%), and 72 (76%) received both. 71 pts (75%) had mastectomies, 24 (25%) had breast conserving surgery. Median residual tumor was 17.5 mm (range 0.1 to 80); 60 pts (63%) were LN+. 78 pts (81%) completed the planned 6 cycles of eribulin. Adjuvant radiation was administered in 28 pts (30%). 3 pts discontinued treatment due to toxicity (1 each with G3 neutropenia, G3 nausea, and unknown grade neuropathy). The most common treatment-related G3/4 adverse events were neutropenia [29 pts (31%)] and leukopenia [10 pts (11%)]. 3 pts (3%) had G3/4 febrile neutropenia and 2 pts (2%) had G3/4 neuropathy. Growth factors were administered to 22 pts (24%). There were no treatment-related deaths. With a median follow up of 19.2 and 14.9 months for Cohorts A and B respectively, the 2 yr DFS probabilities calculated from date of surgery were 61.1 % (95% CI-41.2-76.0) for Cohort A; 82.2% (95% CI-60.2-92.7) for Cohort B. Conclusions: The addition of eribulin is safe and feasible in pts who do not achieve pCR following anthracycline and/or taxane based NAC. At a median follow up of 19.2 months, a statistically significant improvement in the estimated 2 yr DFS was evident in the TN (Cohort A) pts. Citation Format: Yardley DA, Peacock N, Shroff S, Molthrop, Jr DC, Anz B, Daniel BR, Young RR, Weaver R, Harwin W, Webb CD, Ward P, Shastry M, DeBusk LM, Midha R, Hainsworth JD, Burris III HA. A phase 2 study of eribulin in breast cancer not achieving a pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-12-04.

Background: Angiogenesis plays a substantial role in breast cancer development as well as in triple negative breast cancer (TNBC). Sunitinib is an inhibitor of the tyrosine kinase receptors for VEGF, platelet-derived growth factor (PDGF), KIT, RET, and fms-like tyrosine kinase receptor-3 (FLT3). As monotherapy in heavily pretreated breast cancer patients (pts), sunitinib demonstrated a response rate of 15% in TNBC (11% of all pts) with stable disease or better in 16% of all pts. The combination of paclitaxel and carboplatin is ideally suited for further exploration as neoadjuvant chemotherapy for TNBC, based on the established preclinical and clinical sensitivity of TNBC to these cytotoxic agents. This open label, phase I/II trial was designed to evaluate the combination of sunitinib plus paclitaxel and carboplatin as neoadjuvant treatment for locally advanced breast cancer. The primary objective for the phase I portion was to determine the maximum tolerated dose (MTD); these results are presented. Methods: Women with histologically confirmed invasive triple-negative adenocarcinoma of the breast, (defined as <10% staining by IHC for ER/PR; IHC 0–1+ or FISH negative for HER2), with no evidence of metastatic disease and normal LVEF were eligible. All pts received sunitinib (days 1–28), paclitaxel (days 1, 8, 15), and carboplatin (day 1) in 28-day treatment cycles x6. Following 6 cycles, pts had definitive surgery. After ≥2 weeks and evidence of adequate wound healing, maintenance sunitinib 25mg PO daily was initiated to complete a total of 52 weeks. Three dose levels were evaluated as shown in the table below: Doses were escalated in sequential cohorts of pts using standard phase I methodology. MTD was defined as the highest dose level (DL) producing ≤1 dose limiting toxicities (DLTs) in a pt cohort. The MTD identified in the phase I portion of the study will be used in the phase II portion, which will evaluate the efficacy, safety, and tolerability of this combination in pts with locally advanced TNBC. Results: 15 women with TNBC were enrolled between 10/2009 and 2/2011 [median age 53 years (range: 40–78)]. Due to grade 3 neutropenia resulting in the inability to deliver cycle 1 day 15 paclitaxel in the first pt treated at both DLs 1 and 2, these DLs were expanded to 6 pts each. No additional cycle 1 DLTs were noted in the 5 additional pts at either DL. Three pts were accrued to DL 3; there were 2 DLTs noted among these pts (grade 3 febrile neutropenia; grade 3 neutropenia with cycle 2 day 1 treatment delay). However, due to the development of grade 3/4 neutropenia in subsequent cycles in 5 of 6 DL 2 pts, resulting in dose delays and requiring dose reductions, the MTD of this combination was defined as DL 1 (paclitaxel 70mg/m2 (Days 1, 8, 15); carboplatin AUC=5 (Day 1); sunitinib 25mg PO daily). Conclusions: The administration of sunitinib with paclitaxel plus carboplatin as neoadjuvant therapy is feasible with neutropenia defining the MTD of this combination. The phase II portion of this study is ongoing. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-14-29.